The presentation I’m going to give tomorrow morning is on targeting sequencing in endocrine refractory breast cancer. It’s using specimens from a clinical trial, around 4,500 cases from that trial that we were able to perform a targeted sequencing on and actually this morning we had a poster looking at copy number variation in the same dataset. So we’re now able to integrate both the mutational data for point mutations and indels with a copy number variation and start to identify pathways which are associated with hormone refractory cancers which may then give us the ability to stratify patients by those pathways for future targeted therapeutic development.

There are, of course, some very famous pathways out there. Are you finding more of the same or are there any surprises?

We are finding a little bit more of the same. The pathways that we’re identifying are some of the identified pathways like the CCND1-CDK pathway. About 11% of breast cancers that are ER positive have CCND1 copy number variations. What we see is actually if you look at the signalling cassette, which includes the genes CCND2, CCND3 and the CDK4 and CDK6, nearly one in four breast cancers have an alteration in that pathway. So to fully understand the impact of that pathway in the context of endocrine resistance we need to not just look at a single gene but the entire signalling cassette. In parallel with that, alongside that, we have also FGFR1, again a fairly well recognised pathway mutation copy number addition. We see also additions in FGFR2, FGFR3 and 4 but also in some of the FGF ligands. So, again, integrating that gives us a much larger population of patients who are likely to be druggable through those pathways but also now starts to stratify patients into either one or other pathway targeted approach.

I was about to ask about druggable coming from the CDK4 example. Where do you see that going in the near future or can you think of any ways in which this will either expose new targets like you’ve mentioned or give new mechanistic insight into ones that we’ve had before but haven’t quite really been able to corner yet?

It’s a very challenging time in oncology research to try and match these drugs to targetable approaches. We’ve been challenged both in the way we’ve designed studies and executed translational studies to really show a link between a therapeutic drug target and a targeted agent. Part of what we’re showing is that because of the complexity of breast cancer just using a one size fits all approach can actually obscure some of these signals and retro-fitting biomarkers to that to try and engineer a solution has proven to be unsuccessful. So what we’re beginning to generate is data which will allow us to prospectively plan studies, mapping single agent or combinatorial therapies to driver pathways and then interrogate patient response in that context.

What it moves us from is actually the challenge where perhaps the good may be the enemy of the best. Actually getting a response in a broad population is good but if we were to target more effectively the hypothesis would be you would actually enrich the response group and actually then identify patients who should be drugged in a different way and get a better response from a different pathway.

What do you see as the future for being able to sequence someone’s [?? 3:08] profile either in the clinic or getting that information and making it actionable as soon as possible?

In terms of actioning these mutations and copy number alterations in a clinical setting we’re already seeing platforms that can deliver a targeted sequencing approach focussing on known genes, which is where you have a clinical action rather than a discovery setting, which could be deliverable in a clinical setting where the input DNA or RNA amounts are low enough that you could be working from a core biopsy. The turnaround times of 3-5 days are well within the clinical paradigm. We’re seeing that already employed in studies like the NCI MATCH study where these are now impacting the stratification of patients into different therapeutics. As this industry grows we will see more and more of these test programmes which can accommodate the clinical timelines that are required to get patients onto stratified therapies in a reasonable timeframe.